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Protein production, genomic RNA replication, and virion assembly during infection by picornaviruses like human rhinovirus and poliovirus take place in the cytoplasm of infected human cells, making them the quintessential cytoplasmic pathogens. However, a growing body of evidence suggests that picornavirus replication is promoted by a number of host proteins localized normally within the host cell nucleus. To systematically identify such nuclear proteins, we focused on those that appear to re-equilibrate from the nucleus to the cytoplasm during infection of HeLa cells with human rhinovirus via quantitative protein mass spectrometry. Our analysis revealed a highly selective re-equilibration of proteins with known mRNA splicing and transport-related functions over nuclear proteins of all other functional classes. The multifunctional splicing factor proline and glutamine rich (SFPQ) was identified as one such protein. We found that SFPQ is targeted for proteolysis within the nucleus by viral proteinase 3CD/3C, and a fragment of SFPQ was shown to migrate to the cytoplasm at mid-to-late times of infection. Cells knocked down for SFPQ expression showed significantly reduced rhinovirus titers, viral protein production, and viral RNA accumulation, consistent with SFPQ being a pro-viral factor. The SFPQ fragment that moved into the cytoplasm was able to bind rhinovirus RNA either directly or indirectly. We propose that the truncated form of SFPQ promotes viral RNA stability or replication, or virion morphogenesis. More broadly, our findings reveal dramatic changes in protein compartmentalization during human rhinovirus infection, allowing the virus to systematically hijack the functions of proteins not normally found at its cytoplasmic site of replication.

\"Brings together writers originally from Mexico, Bosnia, Iran, Afghanistan, Soviet Ukraine, Hungary, Chile, Ethiopia, and others to make their stories heard ... Their 17 contributions are as diverse as their own lives have been, and yet hold just as many themes in common\"--Amazon.com.

Background The American Shoulder and Elbow Surgeons (ASES) questionnaire was developed to provide a standardized method for evaluating shoulder function. Previous studies have determined the clinical responsiveness of this outcome measure for heterogenous populations or patients with nonoperatively treated rotator cuff disease. Currently, to our knowledge, no studies exist that establish the clinically relevant change in the ASES score after shoulder arthroplasty. Questions/purposes We asked: (1) What are the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) for the ASES score after primary and reverse shoulder arthroplasties? (2) Are the MCID and SCB for the ASES score different between primary and reverse shoulder arthroplasties? (3) What patient-related factors are associated with achieving the MCID and SCB after total shoulder arthroplasty and reverse shoulder arthroplasty? Methods A longitudinally maintained institutional shoulder arthroplasty registry was retrospectively queried for patients who underwent primary shoulder arthroplasty, including anatomic or reverse total shoulder arthroplasty from 2007 to 2013, with a minimum 2-year followup. Seven hundred ninety-four patients were identified and eligible; 304 of these patients did not have 2 years of followup or complete datasets, resulting in a study cohort of 490 patients (62% of the 794 potentially eligible). The MCID and SCB of the ASES score for these patients was calculated using an anchor-based method, using four different anchors measuring satisfaction with work, activities, overall, and activity from the SF-36. The MCID (anchored to somewhat satisfied) and SCB (very satisfied) of the ASES score were calculated for the entire cohort and stratified by arthroplasty type. Multivariate logistic regression of patient-related factors that influence the MCID and SCB achievement was performed. Results The MCID for all patients combined ranged from 6.3 to 13.5; for the overall satisfaction anchor, the MCID was 13.5 ± 4.5 (95% CI, 4.8–22.3). The SCB for the overall cohort ranged from 12.0 to 36.6; for the overall satisfaction anchor, the SCB was 36.6 ± 3.8 (95% CI, 29.1–44.1). There were no differences in the MCID of the ASES score between anatomic and reverse shoulder arthroplasty for any of the anchors (p = 0.159–0.992) or the SCB for any of the anchors (p = 0.467–0.977). Combining anatomic and reverse shoulder arthroplasty in one group, higher preoperative ASES score (odds ratio [OR], 0.96; 95% CI, 0.94–0.98; p < 0.001), having a reverse shoulder arthroplasty (OR, 0.36; 95% CI, 0.16–0.85; p = 0.016), and having rheumatoid arthritis were independent predictors of not achieving an MCID for the ASES 2 years after surgery. Higher preoperative ASES score (OR, 0.91; 95% CI, 0.89–0.92; p < 0.001), a diagnosis of rotator cuff tear arthropathy (OR, 0.14; 95% CI, 0.07–0.30; p < 0.001), a diagnosis of back pain (OR, 0.42; 95% CI, 0.24–0.71); p = 0.002), and living alone (OR, 0.36; 95% CI, 0.19–0.69; p = 0.002) were all independent predictors of not achieving SCB after shoulder arthroplasty. Conclusions Patients with glenohumeral arthritis or rotator cuff tear arthropathy who undergo primary conventional total or reverse shoulder arthroplasty and have at least a nine-point improvement in their ASES score experience a clinically important change, whereas those who have at least a 23-point improvement in their ASES score experience a substantial clinical benefit. High preoperative function was associated with a decreased likelihood of achieving clinically important change after total shoulder arthroplasty. Level of Evidence Level III, therapeutic study.

Objectives To compare interobserver agreement and image quality of 3D T2-weighted fast spin echo (T2w-FSE) L-spine MRI images processed with a deep learning reconstruction (DLRecon) against standard-of-care (SOC) reconstruction, as well as against 2D T2w-FSE images. The hypothesis was that DLRecon 3D T2w-FSE would afford improved image quality and similar interobserver agreement compared to both SOC 3D and 2D T2w-FSE. Methods Under IRB approval, patients who underwent routine 3-T lumbar spine (L-spine) MRI from August 17 to September 17, 2020, with both isotropic 3D and 2D T2w-FSE sequences, were retrospectively included. A DLRecon algorithm, with denoising and sharpening properties was applied to SOC 3D k-space to generate 3D DLRecon images. Four musculoskeletal radiologists blinded to reconstruction status evaluated randomized images for motion artifact, image quality, central/foraminal stenosis, disc degeneration, annular fissure, disc herniation, and presence of facet joint cysts. Inter-rater agreement for each graded variable was evaluated using Conger’s kappa ( κ ). Results Thirty-five patients (mean age 58 ± 19, 26 female) were evaluated. 3D DLRecon demonstrated statistically significant higher median image quality score (2.0/2) when compared to SOC 3D (1.0/2, p < 0.001), 2D axial (1.0/2, p < 0.001), and 2D sagittal sequences (1.0/2, p value < 0.001). κ ranges (and 95% CI) for foraminal stenosis were 0.55–0.76 (0.32–0.86) for 3D DLRecon, 0.56–0.73 (0.35–0.84) for SOC 3D, and 0.58–0.71 (0.33–0.84) for 2D. Mean κ (and 95% CI) for central stenosis at L4-5 were 0.98 (0.96–0.99), 0.97 (0.95–0.99), and 0.98 (0.96–0.99) for 3D DLRecon, 3D SOC and 2D, respectively. Conclusions DLRecon 3D T2w-FSE L-spine MRI demonstrated higher image quality and similar interobserver agreement for graded variables of interest when compared to 3D SOC and 2D imaging. Key Points • 3D DLRecon T2w-FSE isotropic lumbar spine MRI provides improved image quality when compared to 2D MRI, with similar interobserver agreement for clinical evaluation of pathology . • 3D DLRecon images demonstrated better image quality score (2.0/2) when compared to standard-of-care (SOC) 3D (1.0/2), p value < 0.001; 2D axial (1.0/2), p value < 0.001; and 2D sagittal sequences (1.0/2), p value < 0.001 . • Interobserver agreement for major variables of interest was similar among all sequences and reconstruction types. For foraminal stenosis, κ ranged from 0.55 to 0.76 (95% CI 0.32–0.86) for 3D DLRecon, 0.56–0.73 (95% CI 0.35–0.84) for standard-of-care (SOC) 3D, and 0.58–0.71 (95% CI 0.33–0.84) for 2D .

Background: Clostridioides difficile infection (CDI) has emerged as a prevalent and recurrent antibiotic-associated infection. Fecal microbiota transplantation (FMT) is the most effective treatment for recurrent CDI (rCDI). Despite high success rates, FMT is ineffective in 5%–20% of cases. Factors associated with failure have not been clearly defined. Objectives: In this study, we seek to identify factors predictive of FMT failure. Design: Retrospective cohort study. Methods: A retrospective chart review was conducted on adult patients who were screened at the Complicated C. difficile Clinic at the University of Virginia Health System and received FMT for rCDI between 2013 and 2022. The primary outcome was failure of FMT, defined as either rCDI or all-cause death within 1 year. Results: In total, 240 patients underwent FMT: 70.4% were female, the median age was 68, and the median episode of CDI was 4. A total of 24.6% experienced failure within 1 year (18.3% had rCDI and 7.1% died). Age 70 or older (odds ratio (OR) = 2.66 (1.29–5.67)), ⩾4 episodes of CDI (OR = 3.13 (1.47–7.09)), and diabetes mellitus (OR = 2.82 (1.25–6.50)) were associated with failure on multivariate analysis. Conclusion: Our study shows that FMT remains an effective treatment for rCDI. We highlight several factors associated with FMT failure, such as older age, ⩾4 episodes of CDI, and diabetes mellitus, and the need for additional research to clearly define causality. Plain language summary Factors associated with failure of fecal microbiota transplant for recurrent Clostridioides difficile infection Clostridioides difficile infection (CDI) is a common diarrheal infection associated with antibiotic use. It is commonly treated with antibiotics, and in patients with recurrent CDI (rCDI), fecal microbiota transplantation (FMT) is the most effective treatment. Despite high success rates, FMT is ineffective in 5–20% of cases. Factors associated with failure have not been clearly defined. In this study, we seek to better understand factors predictive of FMT failure. We conducted a retrospective chart review, looking at electronic medical records of 240 adult patients. All patients were screened at the Complicated C. difficile Clinic at the University of Virginia Health System and received FMT for rCDI between 2013 and 2022. The primary outcome was failure of FMT, defined as either rCDI or all-cause death within one year. Of the 240 patients who underwent FMT: 70.4% were female, median age was 68, and median episodes of CDI was 4. 24.6% experienced failure within the year (18.3% had rCDI and 7.1% died). Age 70 or older, ≥4 episodes of CDI, and diabetes mellitus were significantly associated with FMT failure. Our study shows that FMT remains an effective treatment for rCDI. We highlight several factors associated with FMT failure and the need for additional research to clearly define causality.

Spherical nucleic acids (SNAs) are nanostructures formed by chemically conjugating short linear strands of oligonucleotides to a nanoparticle template. When made with modified small interfering RNA (siRNA) duplexes, SNAs act as single-entity transfection and gene silencing agents and have been used as lead therapeutic constructs in several disease models. However, the manner in which modified siRNA duplex strands that comprise the SNA lead to gene silencing is not understood. Herein, a systematic analysis of siRNA biochemistry involving SNAs shows that Dicer cleaves the modified siRNA duplex from the surface of the nanoparticle, and the liberated siRNA subsequently functions in a way that is dependent on the canonical RNA interference mechanism. By leveraging this understanding, a class of SNAs was chemically designed which increases the siRNA content by an order of magnitude through covalent attachment of each strand of the duplex. As a consequence of increased nucleic acid content, this nanostructure architecture exhibits less cell cytotoxicity than conventional SNAs without a decrease in siRNA activity.

Background and purposeThree-dimensional (3D) imaging of the spine, augmented with AI-enabled image enhancement and denoising, has the potential to reduce imaging times without compromising image quality or diagnostic performance. This work evaluates the time savings afforded by a novel, rapid lumbar spine MRI protocol as well as image quality and diagnostic differences stemming from the use of an AI-enhanced 3D T2 sequence combined with a single Dixon acquisition.Materials and methodsThirty-five subjects underwent MRI using standard 2D lumbar imaging in addition to a “rapid protocol” consisting of 3D imaging, enhanced and denoised using a prototype DL reconstruction algorithm as well as a two-point Dixon sequence. Images were graded by subspecialized radiologists and imaging times were collected. Comparison was made between 2D sagittal T1 and Dixon fat images for neural foraminal stenosis, intraosseous lesions, and fracture detection.ResultsThis study demonstrated a 54% reduction in total acquisition time of a 3D AI-enhanced imaging lumbar spine MRI rapid protocol combined with a sagittal 2D Dixon sequence, compared to a 2D standard-of-care protocol. The rapid protocol also demonstrated strong agreement with the standard-of-care protocol with respect to osseous lesions (κ = 0.88), fracture detection (κ = 0.96), and neural foraminal stenosis (ICC > 0.9 at all levels).Conclusion3D imaging of the lumbar spine with AI-enhanced DL reconstruction and Dixon imaging demonstrated a significant reduction in imaging time with similar performance for common diagnostic metrics. Although previously limited by long postprocessing times, this technique has the potential to enhance patient throughput in busy radiology practices while providing similar or improved image quality.

Background Race is an important predictor of TKA outcomes in the United States; however, analyses of race can be confounded by socioeconomic factors, which can result in difficulty determining the root cause of disparate outcomes after TKA. Questions/purposes We asked: (1) Are race and socioeconomic factors at the individual level associated with patient-reported pain and function 2 years after TKA? (2) What is the interaction between race and community poverty and patient-reported pain and function 2 years after TKA? Methods We identified all patients undergoing TKA enrolled in a hospital-based registry between 2007 and 2011 who provided 2-year outcomes and lived in New York, Connecticut, or New Jersey. Of patients approached to participate in the registry, more than 82% consented and provided baseline data, and of these patients, 72% provided 2-year data. Proportions of patients with complete followup at 2 years were lower among blacks (57%) than whites (74%), among patients with Medicaid insurance (51%) compared with patients without Medicaid insurance (72%), and among patients without a college education (67%) compared with those with a college education (71%). Our final study cohort consisted of 4035 patients, 3841 (95%) of whom were white and 194 (5%) of whom were black. Using geocoding, we linked individual-level registry data to US census tracts data through patient addresses. We constructed a multivariate linear mixed-effect model in multilevel frameworks to assess the interaction between race and census tract poverty on WOMAC pain and function scores 2 years after TKA. We defined a clinically important effect as 10 points on the WOMAC (which is scaled from 1 to 100 points, with higher scores being better). Results Race, education, patient expectations, and baseline WOMAC scores are all associated with 2-year WOMAC pain and function; however, the effect sizes were small, and below the threshold of clinical importance. Whites and blacks from census tracts with less than 10% poverty have similar levels of pain and function 2 years after TKA (WOMAC pain, 1.01 ± 1.59 points lower for blacks than for whites, p = 0.53; WOMAC function, 2.32 ± 1.56 lower for blacks than for whites, p = 0.14). WOMAC pain and function scores 2 years after TKA worsen with increasing levels of community poverty, but do so to a greater extent among blacks than whites. Disparities in pain and function between blacks and whites are evident only in the poorest communities; decreasing in a linear fashion as poverty increases. In census tracts with greater than 40% poverty, blacks score 6 ± 3 points lower (worse) than whites for WOMAC pain (p = 0.03) and 7 ± 3 points lower than whites for WOMAC function (p = 0.01). Conclusions Blacks and whites living in communities with little poverty have similar patient-reported TKA outcomes, whereas in communities with high levels of poverty, there are important racial disparities. Efforts to improve TKA outcomes among blacks will need to address individual- and community-level socioeconomic factors. Level of Evidence Level III, therapeutic study.

BACKGROUND: Discogenic chronic low back pain (cLBP) and radiculopathy are the most prevalent causes of disability worldwide. Older spine treatments often lack reliability and are associated with adverse events. Among surgical treatment options, discectomies weaken discs, and fusions cause direct damage to adjacent discs, so both treatments accelerate disc degeneration. Other regenerative medicine treatments, including “stem cell” (centrifuged bone marrow aspirate, BMC), and platelet-rich plasma (PRP), lack fibrin’s bio-adhesive properties. Specifically, fibrin is a strong bio-adhesive, so it immediately integrates into disc defects and binds there, becoming a part of the disc and facilitating new disc tissue growth. OBJECTIVES: To evaluate the safety and efficacy of this new pragmatic algorithm that both diagnoses and treats cLBP by (i) first identifying annulus fibrosus tears (fissures) in the region of symptoms and (ii) subsequently treating those tears by introducing fibrin to seal them and facilitate new tissue growth. STUDY DESIGN: Retrospective cohort study that prospectively reported validated measures in a registry. SETTING: Private, single-center, specialized, interventional pain management institution. METHODS: The patients we decided to observe had suffered from cLBP with or without radiculopathy symptoms in their legs for greater than 6 months. Prior to enrollment, all patients underwent physical therapy and at least 4 invasive treatments without relief. Failed treatments included BMC or PRP injections, intradiscal or intraarticular zygapophyseal joints, or combinations of both. Fluoroscopically guided epidural injections of corticosteroids or PRP were additional failed treatments, as were radiofrequency neurotomies in the medial branch. Candidacy for enrollment was based on meeting the aforementioned criteria and by having magnetic resonance image (MRI) screenings (1.5 T) and plain-film radiographs performed 6 months before treatment. In addition, those MRI screenings and radiographs had to rule out the following concomitant conditions: (i) carcinoma, (ii) fracture, (iii) instability, or (iv) severe vertebral canal or intervertebral foramen stenosis. RESULTS: Significant improvement was demonstrated at one, 2, and 3 years after treatment in all outcome measures. The mean duration of low back pain prior to treatment was 11.2 years. Patients’ mean age was 56 years. Thirty percent of the patients were female, and 70% were male. Both the failed surgery cohort and nonsurgery cohort demonstrated significant improvement after fibrin treatment, with the failed surgery cohort realizing greater relative improvement. Significant improvements in the Oswestry disability index (ODI), visual analog scale, and PROMIS® (mental and physical) scores were consistent across age, gender, comorbidity, and exposure status. At the 12-month follow-up, 50% of patients achieved minimal clinically important differences utilizing the ODI. No severe adverse events were reported. LIMITATIONS: Limitations include patient demographic factors, outcome-measure sensitivity, and that the outcomes were reported prospectively and calculated retrospectively as one-, 2-, and 3-year time frames were attained. Although categorical analyses comparing the prior surgical cohort to the nonsurgical cohort were performed, other pre-enrollment treatments were not categorized for comparison. CONCLUSIONS: Intra-annular fibrin bio-adhesive sealant demonstrates the ability to be an effective treatment for alleviating discogenic cLBP and radiculopathy for at least 3 years, even in patients who all failed multiple prior treatments, including discectomy, fusion, disc PRP, or BMC. The results suggest the benefits of fibrin sealant. Future investigations to consider include a randomized double-blind controlled trial and further categorical analyses. KEY WORDS: Low back, radiculopathy, fibrin, disc herniation, degenerative disc, regenerative, annulargram, annulogram